Inherited deficiency of the enzyme purine nucleoside phosphorylase (PNP) results in selective and severe T lymphocyte depletion which appears to be mediated by its purine deoxyribonucleoside substrate, 2'-deoxyguanosine. This observation has provided a strong rationale for the use of inhibitors of this enzyme and/or analogues of 2'-deoxyguanosine which are not substrates for PNP as selective chemotherapeutic agents in lymphoproliferative malignancies. We propose to investigate the cytotoxic and metabolic effects of the known PNP inhibitor, 8-aminoguanosine, and its metabolite, 8-aminoguanine, on cultured human lymphoblast cell lines and in a Balb/c mouse model. Using high pressure liquid chromatography, we will determine the effects of inhibiting PNP in the absence and presence of 2'-deoxyguanosine on ribonucleotide and deoxyribonucleotide pools and on nucleic acid synthesis in cultured cells, as well as on the nucleotide pools and on nucleic acid synthesis in cultured cells, as well as on the plasma and urinary levels of ribo- and deoxyribonucleosides in the mouse. In addition, we will screen both guanosine and 2'-deoxyguanosine analogues synthesized by Dr. Leroy Townsend for PNP inhibitory activity, characterizing the kinetics of inhibition using purified enzymes, and for selective toxicity for T lymphoblasts in vitro. The chemotherapeutic potential of these compounds will be evaluated using a variety of mouse lymphoid tumor lines. Finally, we will determine the susceptibility of human leukemic cells of both lymphoid and non-lymphoid origin to 2'-deoxyguanosine and its analogues in the absence and presence of PNP inhibitors. We will then attempt to prospectively identify sensitive cell types on the bases of 1) standard cytochemical and immunologic markers and 2) activities of enzymes in the purine metabolic pathway. These studies should lead to the identification of new pharmacologic agents which, by virtue of their specific effects on the purine salvage pathway, have highly selective chemotherapeutic effects.